CN103002856B

CN103002856B - Freezing, thaw and store the system and method used in processing biopharmaceutical materials

Info

Publication number: CN103002856B
Application number: CN201080061970.2A
Authority: CN
Inventors: J·卡廷; I·盖伊; O·W·赖夫
Original assignee: Sartorius Stedim North America Inc
Current assignee: Sartorius Stedim North America Inc
Priority date: 2009-11-23
Filing date: 2010-11-23
Publication date: 2015-08-05
Anticipated expiration: 2030-11-23
Also published as: CN103002856A; CN104719284B; WO2011063381A3; EP2503978B1; CN104719284A; WO2011063381A2; US8371132B2; US20110120667A1; EP2503978A2

Abstract

A kind of for system (5) that is freezing, that thaw, transport or store processing biopharmaceutical materials, it comprises container (10), keeper and multiple heat transfer element (30).Container (10) is configured to preserve processing biopharmaceutical materials wherein.Keeper (15,415,416,515) has the chamber (550,650) for receiving vessel, and comprises the inner surface defining chamber (550,650).The outer surface of multiple depression (20,420,621,622,623) contacting container and being received in chamber (550,650).Each depression (20,420,621,622,623) of these depressions (20,420,621,622,623) comprises pocket cavity (122,421).Heat transfer element (30) controls the temperature of the processing biopharmaceutical materials be held in container (10) on one's own initiative, and is received in pocket cavity (122,421).

Description

Freezing, thaw and store the system and method used in processing biopharmaceutical materials

Technical field

Present invention relates in general to processing biopharmaceutical materials, store method and system, and relate more specifically to for system and method that is freezing, the processing biopharmaceutical materials that stores, transports and thaw.

Background technology

Processing biopharmaceutical materials be kept at its manufacture, use, transport, store and sell in be all important.Such as, processing biopharmaceutical materials is frequently by between the treatment steps and preserve memory period is freezing.Similarly, as a part for development technology, processing biopharmaceutical materials is often freezing to be improved quality with thawing or simplifies development technology.Processing biopharmaceutical materials also may need to store under a certain temperature range and shipment.

When frozen biopharmaceutical material, be desirably in the oeverall quality that retains processing biopharmaceutical materials when not having processing biopharmaceutical materials to degenerate significantly and especially pharmacologically active.

The preservation of processing biopharmaceutical materials, especially in enormous quantities, often relates to and the container comprising liquid biopharmaceutical material is positioned over the ingressive fridge of cabinet freezer, chest freezer or people and allows processing biopharmaceutical materials freezing.Particularly, usual volume is more than 1 liter and can be usually positioned on the shelf in the ingressive fridge of cabinet freezer, chest freezer or people by the container up to more than 10 liters, and allows processing biopharmaceutical materials freezing.These containers can be rustless steel container, plastic bottle or carboy or plastic bag.They are filled to designated volume usually, to allow freezing and expand and be then conveyed into fridge from negative 20 DEG C in usual scope to bearing 70 DEG C or lower temperature.

Disposable large volume storage container, such as plastic bag or other flexible containers, often impaired, cause the loss of processing biopharmaceutical materials.Especially, the volumetric expansion of processing biopharmaceutical materials between pool period can produce excessive pressure in the bag of excessively filling or in the depression of the blocking liquid of contiguous bag material, may cause breaking or damage to its integrity of bag.And; this disposable container such as plastic bag is freezing at it, thaw or the manipulation of In transit often can cause it impaired, such as due to operator's error or in using to the vibrations caused by insufficient protection of bag, wearing and tearing, impact or other maloperation events.

Similarly, they remove from cryoprobe by the thawing to relate to of large volume processing biopharmaceutical materials, and allow them at room temperature to thaw.In some cases, thaw and also can cause product loss.In addition, in some cases, the quick-thawing of processing biopharmaceutical materials may produce than less product loss that slowly thaws.And, also can the temperature of desired control processing biopharmaceutical materials during course of defrosting, because the temperature that some processing biopharmaceutical materials are exposed to rising in some cases also can cause product loss.Such as, may expect still to be in liquid and solid form while that a kind of processing biopharmaceutical materials of thawing being maintained at about 0 DEG C between its frost free period.When expecting to thaw, processing biopharmaceutical materials must be protected from may due to the impact of container or caused damage of breaking.

In another example, the rustless steel container of jacket layer receives processing biopharmaceutical materials wherein for freezing and thaw.In another example, bag is received in board-like fridge, to control the temperature of the processing biopharmaceutical materials in this bag.But jacket layer rustless steel container needs significant cost of investment and there is the danger of cross-contamination.And, use board-like fridge to control the temperature of the processing biopharmaceutical materials in bag or flexible container, then need the remarkable cost of investment of board-like fridge self.And the flexible container used together with this board-like fridge lacks robustness or ruggedness, and thus may in use damage.

Known a kind of thermally insulated container from document No.WO-A-01/02268, it comprises and will be maintained at the payload volume in predetermined temperature range.Described container comprise cold bin and and the heat setting glue of payload volume thermo-contact to be used as thermal boundary between cold bin and described payload volume.It also comprises Temperature-controlled appliance,---such as example Peltier sensor, it is installed between cold bin and heat setting glue in order to control from gel to the heat flow of cold bin.

Document No.US-B1-6 220 051 describes a kind of cooling system, it control box comprising the liquefied gas cylinder of being filled by liquefied gas, the keeper keeping liquefied gas cylinder and be installed on keeper.Control box provides nozzle, for liquefied gas jet flow direct ground connection is spurted into container or spurted into the cooling segment of container.

Document No.WO-A1-98/34078 also discloses a kind of heat transfer system for heating or cooling medium.Especially, a structure being positioned internal tank is used for container to be segmented into multiple compartment, and has the far-end of closely pressing close to inner surface of container and introduce heat in medium or the heat bridge of therefrom deriving to allow to be formed.

Document No.US-A-3942668 describes a kind of elongated vessel, and it comprises circular elongated concave member and the hollow male element of circular elongated, and male element is used for slidably and rotatably inserting concave member.Described elongated vessel to be inserted in tank and to be positioned in liquid coolant, under being maintained at predetermined temperature.

Document No.WO-A1-97/29331 discloses a kind of chiller assembly bottle by enzyme sample load being maintained at the state of cooling.This chiller assembly comprises the foam block of the well type part had for sample bottle being held in erection position, outer foam box and lid.Foam block is positioned in outer foam box.Then lid is positioned on the top of outer foam box, further to completely cut off for foam block provides.In use, foam block via filler opening by flowing fluid ratio as water is filled, and then freezing.Bottle is positioned in the well type part of frozen foam block, keeps cooling to make the content of bottle when being positioned in the room with ambient temperature.

This is also from prior art document US3, 942, 668, US4, 011, 736, US5, 103, 651, US5, 548, 967, US5, 638, 686, US-B 1-6, 196, 296, US-B 1-6, 220, 051, US-B 1-6, 302, 327, US-B1-6, 453, 683, US-B2-6, 775, 473, US-B2-6, 786, 054, US-B2-6, 635, 414, US-B2-6, 945, 056, US-B2-6, 996, 995, US-B2-7, 055, 583, US-B2-7, 104, 074, US-B2-7, 137, 261, US-B2-7, 263, 855, US-B2-7, 337, 908, US-B2-7, 353, 658, US-A1-2004/0226309, US-A1-2007/0062670, US-A1-2008/0000624, GB-A-2 236 694, WO97/29331, known in WO98/34078 and WO01/02268.

Thus, need a kind of for freezing, thaw and store the system and method for processing biopharmaceutical materials, comprise and can be used for freezing, the container that thaws, transport and store of processing biopharmaceutical materials and the keeper of this container.

Summary of the invention

The present invention provides a kind of for system that is freezing, that thaw, transport or store processing biopharmaceutical materials in first, and it comprises: for keeping the case of processing biopharmaceutical materials wherein; Have the keeper in the keeper chamber for receiving described container, described keeper comprises the depression that its inner surface defines described keeper chamber.Described depression contacts the outer surface of described case, and described depression comprises pocket cavity.And this system also comprises the heat transfer element of the temperature for controlling the processing biopharmaceutical materials be held in described case on one's own initiative, and described heat transfer element is received in described pocket cavity.

According to an embodiment, this system comprises structure and inserts relative to described pocket cavity and remove the mechanism of described heat transfer element.

According to an embodiment, described depression is included in the opening for receiving described heat transfer element on its top.

According to an embodiment, described pocket configurations is for keep liquid wherein, and liquid promotes that the heat transfer between the described heat transfer element that is received in described pocket cavity and described keeper is to control the temperature of the processing biopharmaceutical materials be held in described container.

According to an embodiment, described keeper comprises keeper wall, and described keeper wall is spill when processing biopharmaceutical materials is in liquid state towards described chamber.

According to an embodiment, this system also comprises for determining when described heat transfer element is properly positioned to the alignment sensor in described pocket cavity.

According to an embodiment, this system also comprises for determining the sensor when described chamber is filled fully by liquid.

According to an embodiment, this system also comprises the supplemental heater of separating with described heat transfer element, and its liquid heated up in described pocket cavity does not have the passage of ice thus formed to leave path for a part of liquid to maintain during refrigeration operation.

According to an embodiment, this system also comprises and is received in supplemental heater in described case to maintain the passage not having frozen biopharmaceutical material in described case.

According to second aspect, the invention provides a kind of for system that is freezing, that thaw, transport or store processing biopharmaceutical materials, described system comprises: for keeping the case of processing biopharmaceutical materials wherein; Have the keeper of multiple depression, depression contacts the outer surface of described case, and each depression of described multiple depression comprises pocket cavity; Described keeper has the keeper chamber for receiving described case, and described multiple depression comprises the inner surface defining described keeper chamber, and described inner surface comprises two contact surfaces of the opposite flank contacting described case.

According to an embodiment, each depression of described multiple depression is included in the opening for receiving heat transfer element on its top, and described heat transfer element is for controlling the temperature of the processing biopharmaceutical materials be held in described container.

According to an embodiment, each pocket configurations of described multiple depression is for keep liquid wherein, and liquid promotes to be received in heat transfer between described heat transfer element in described pocket cavity and the wall of each depression to control the temperature of the processing biopharmaceutical materials be held in described case when described heat transfer element is received in described chamber.

According to an embodiment, described keeper comprises keeper wall, and described keeper wall is spill towards each other when processing biopharmaceutical materials is in liquid state.

According to an embodiment, each depression of described multiple depression is tapered with the insertion being easy to described heat transfer element with remove from described opening.

According to the 3rd aspect, the invention provides a kind of for freezing, thaw or store the method for processing biopharmaceutical materials, described method comprises: be received in the keeper chamber of keeper by keeping the case of processing biopharmaceutical materials; The depression of keeper contacts the outer surface of described case, and depression comprises pocket cavity; Heat transfer element is received in pocket cavity; And the temperature of Heat Transfer Control element is on one's own initiative to control the temperature being held in processing biopharmaceutical materials in case.

According to an embodiment, the method also comprises and inserts the liquid into pocket cavity and wherein the control of temperature comprises the temperature of Heat Transfer Control element with frozen biopharmaceutical material, and the control of temperature causes the freezing of liquid thus promotes the heat transfer between heat transfer element and the wall of depression.

According to an embodiment, the method also comprises introduces depression to provide the passage not having ice during the refrigeration operation caused by the temperature due to Heat Transfer Control element by supplemental heater.

According to an embodiment, the method also comprises introduces case to provide the passage not having frozen biopharmaceutical material during the refrigeration operation caused by the temperature due to Heat Transfer Control element by supplemental heater.

According to an embodiment, the method also comprise insert the liquid into pocket cavity and wherein the control of temperature comprise control liquid temperature to promote heat transfer between heat transfer element and the wall of depression thus the temperature of control processing biopharmaceutical materials.

For a method for mixed biologic biopharmaceutical material, described method comprises: be received in the keeper chamber of keeper by keeping the case of processing biopharmaceutical materials; Described keeper comprises multiple depressions of the outer surface contacting described case, and each depression of described multiple depression comprises pocket cavity; The inner surface of described multiple depression defines keeper chamber; And mobile keeper is to cause the mixing of the processing biopharmaceutical materials in case.

According to an embodiment, described movement comprises periodically moves keeper.

According to an embodiment, described movement comprises moves keeper randomly.

According to an embodiment, the method also comprise heat transfer element is received in pocket cavity and on one's own initiative the temperature of Heat Transfer Control element to control the temperature of the processing biopharmaceutical materials be held in case.

According to an embodiment, the method also comprises to be introduced depression by supplemental heater thus provides the passage not having ice during being provided in the refrigeration operation caused by the temperature of Heat Transfer Control element.

According to an embodiment, the method also comprises to be introduced case by supplemental heater thus provides the passage not having frozen biopharmaceutical material during being provided in the refrigeration operation caused by the temperature of Heat Transfer Control element.

According to the 4th aspect, the invention still further relates to a kind of method for mixed biologic biopharmaceutical material, described method comprises: be received in the keeper chamber of keeper by keeping the case of processing biopharmaceutical materials; Multiple depressions of keeper contact the outer surface of described case, and each depression of described multiple depression comprises pocket cavity; The inner surface of described multiple depression defines keeper chamber; And remove processing biopharmaceutical materials in the primary importance of case from case and be reintroduced back to processing biopharmaceutical materials in the second position to cause the mixing of processing biopharmaceutical materials.

According to the 5th aspect, the invention provides a kind of method for mixed biologic biopharmaceutical material, described method comprises: be received in the keeper chamber of keeper by keeping the case of processing biopharmaceutical materials; Multiple depressions of keeper contact the outer surface of described case, and each depression of described multiple depression comprises pocket cavity; The inner surface of described multiple depression defines keeper chamber; And mobile mixed organization thus cause the mixing of processing biopharmaceutical materials in processing biopharmaceutical materials in case.

According to an embodiment, the movement of mixed organization comprises the probe in mobile processing biopharmaceutical materials, and this probe has and is connected to the plate with one or more angled aperture of axle orthogonally and the longitudinal axis along this axle drives this axle under linear course.

According to an embodiment, the method also comprise probe in frozen biopharmaceutical material and processing biopharmaceutical materials thaw start time heated probe to form the empty working volume not having ice.

According to an embodiment, mobile mixed organization comprises the propeller in rotating biological biopharmaceutical material.

According to an embodiment, the method also comprise propeller in frozen biopharmaceutical material and processing biopharmaceutical materials thaw start time heating propeller to form the empty working volume not having ice.

According to an embodiment, the method also comprise heat transfer element is received in pocket cavity and on one's own initiative Heat Transfer Control element temperature with control to be held in case temperature.

Accompanying drawing explanation

Be considered as theme of the present invention especially point out in the claim at description conclusion place and state clearly.Foregoing and other feature of the present invention and advantage will be easy to understand from below in conjunction with accompanying drawing detailed description of the preferred embodiment, in the accompanying drawings:

Fig. 1 is the perspective view according to the keeper (described keeper is received in supporting plate base portion) for receiving the container preserving processing biopharmaceutical materials of the present invention;

Fig. 2 is the bag of keeper for heat transfer element being inserted Fig. 1 and controls the side perspective view of the process of the temperature of the processing biopharmaceutical materials be held in keeper;

Fig. 3 is through the vertical cross section of the keeper of Fig. 1, shows heat-transfer fluid and flows through heat transfer element in the depression be positioned on the side of keeper;

Fig. 3 A is through the level cross-sectionn of the keeper of Fig. 1;

Fig. 4 is the perspective view of keeper when not having container to be arranged in its chamber of Fig. 1;

Fig. 5 is the block diagram of the keeper 1 that Fig. 1 is shown, it receives the heat transfer element being bonded to pump and controller, and heat transfer element reduces the depression into keeper from elevator;

Fig. 6 is the perspective view of three keepers as shown in Figure 1, and they draw as it having cover plate on supporting plate base portion together;

Fig. 7 is the side cross-sectional view of a part for the keeper of Fig. 1, and the heat transfer element in the depression be received on the outer surface of keeper is shown;

Fig. 8 is the side cross-sectional view of the keeper of Fig. 1, shows the heat transfer element be received in its depression, and supplementary heating element;

Fig. 9 is the perspective view of multiple according to another embodiment of the present invention keeper, and the top removal of one of them is to illustrate the chamber receiving two depressions wherein;

Figure 10 is the top orthogonal view of multiple keepers of Fig. 9, and the container be received in the keeper of top removal is shown;

Figure 11 is the lateral elevational view of multiple keepers of Fig. 9;

Figure 12 is the perspective view of the keeper according to different embodiments of the invention;

Figure 13 is the perspective view being configured to the container be received in the keeper of Figure 12; And

Figure 14 is the perspective view of the another embodiment according to container of the present invention.

Detailed description of the invention

According to principle of the present invention, provide for freezing, thaw and store the system and method for processing biopharmaceutical materials.

In the exemplary embodiment shown in Fig. 1-4, to show for cooling, the system 5 of freezing, processing biopharmaceutical materials of preserving, process and thaw.This system can comprise sterile chamber, and such as in the flexible container 10 of bag form, it is configured to comprise processing biopharmaceutical materials, and to be configured to be received in support and/or operator guards (such as keeper 15) and to be supported by it.Keeper can be received in base portion 17, and base portion 17 has for receiving and multiple depression of the bottom 119 of support holder 15 or groove 117.

Keeper 15 can be configured to the shape protecting and maintain flexible container.As Figure 1-3, flexible container can be complied with or the shape that conforms to mutually with the geometry of keeper.Keeper 15 also comprises one or more outside depression 20, for receiving one or more heat transfer element 30.As Fig. 3 and 7 illustrates best, heat-transfer fluid capable of circulation through heat transfer element (such as, via pump) and thus through each depression, to cause the freezing of the processing biopharmaceutical materials in the container that is held in and remains in keeper or to thaw.Water or another fluid can be arranged at (that is, around heat transfer element) in depression 20 so that heat transfer element and keeper outer surface 22 between heat transfer.The connection of depression 20 by the outer surface 22 of cave structure element 25 to keeper 15 or the monomer molding relative to the latter and formed.The chamber 122 of each depression can be defined by the inner surface 125 of outer surface 22 and each structural detail 25 as shown in Figure 4.

Keeper 15 can be formed by plastics, and also can be made up of metal such as rustless steel or aluminum.For cryogenic applications, polyethylene is preferred.By using plastics, can utilize the manufacturing technology of such as rotational moulding, blowing and thermoforming and so on, this makes to obtain significant cost and weight minimizing and larger design flexibility.

Keeper 15 can monolithically be formed (such as, having 5 monomer sidepieces and an open top), or it can be formed as two or more parts that can be connected to each other, such as concha Anodonta seu Cristaria design.This separate section can be mirror image each other, and these parts that various piece can be allowed to carry out is nested, thus increase being packed bulk density during sky.Cave structure element 25 also monolithically can be formed relative to integral type keeper (such as keeper 15), or this multi-piece type keeper can be formed as mirror image each other.

Keeper 15 has inner surface 40, and it defines the chamber 50 of receiving vessel 10 and the shape that conforms to the geometry of container 10.Inner surface 40 can comprise relative contact surface 41, and it is contacting container 10 in the opposite sides of container 10, and it can extend to bottom 119 from the top 118 of keeper 15.Keeper 15 has open top 23 to allow to lead to the path in chamber 50, for installing container 10 before filling and removing after draining.Keeper 15 can comprise be allowed for processing biopharmaceutical materials filling, drain, the port of sampling etc. runs through feature (such as opening, valve) wherein.Keeper 15 has the seam of additionally permission container 15 alternatively to avoid the feature (such as, groove or chamber) of pressure-bearing during shipment and manipulation.Keeper 15 also can have the feature of such as pipeline clip or protection depression and so on, with the parts of locating, protecting and/or outside tissue container, and such as pipeline, fixture, adapter, valve, instrument, filter etc.

As shown, keeper 15 comprises one or more depression 20, and they can be positioned at it, and longitudinally surface is upper or can be positioned at substantially on its all outer surfaces.Depression will preferably occupy surface area large as far as possible, to promote the heat transfer element that is held in wherein and to be held in the heat transfer between the processing biopharmaceutical materials in container 10.Each depression has opening 26 at its top end, with certain part allowing each depression to receive one of them removable heat transfer element 30.Each depression can extend to bottom 119 from the top 118 of keeper 15.

And depression provides structural rigidity at the junction point place (that is, two walls in double-walled construction are taken to together to form rib at contact point place) of the outer surface 22 of cave structure element 25 to keeper 20.Processing biopharmaceutical materials in fluid pressure, external force and container 10 can be resisted or overcome to the connection of the outer surface 22 of cave structure element 25 to keeper 20 in the expansion of freezing and period of thawing and contraction.As shown in Figure 4, cave structure element 25 monolithically can be formed as single monomer segment 28, be connected to outer surface 22 to make female 27 and depression forming section 29 deviate from outer surface 22 ground extend to form depression 20.

And depression receives heat transfer element, to provide minimum interval between the heating/cooling surface (that is, the outer surface of heat transfer element) in keeper 15 and container 10 and processing biopharmaceutical materials.Cave structure element 25 can be connected to outer surface 22, is liquid-tight (such as, via sealing, being tightly connected or unibody construction) to make depression.This allows each depression to keep water or another liquid, thus promotes the heat transfer between the heat transfer element 30 in depression 20 and keeper 15, thus promotes the heat transfer relative to the processing biopharmaceutical materials be held in container 10.

More specifically, when heat transfer element 30 inserts depression, between the inner surface 125 that annular gap is present in each heat transfer element and each cave structure element 25 and outer surface 22.This gap expects, so that heat transfer element is introduced depression and from wherein removing, it is by allowing to have gap around each heat transfer element.But any this gap is by minimizing heat transfer element and keeper 15 and thus reduce and be held in the heat transfer between the processing biopharmaceutical materials in container 10.Liquid (such as water) is introduced depression (such as depression 20) can provide from heat transfer element to outer surface 22 and thus container 10 and be held in the heat bridge of processing biopharmaceutical materials wherein.Thus, any heat transfer is reduced by and allows gap be full of flowing fluid ratio to avoid as water or reduce.Liquid can introduce depression via liquid distribution manifold 31, and liquid distribution manifold 31 also can allow the emptying of its this depression passed, such as shown in Figure 3.

After being held in the liquid freezing in depression 20, also expect any space or gap the minimizing between frozen liq and outer surface 22 that air exclusion effect can be provided.The heat transfer that any this gap will reduce between heat transfer element 30 and the content of container 15.Inner surface 125 and/or the heat transfer element 30 of outer surface 22, cave structure element 25 can comprise projection or surface of the texture, to promote the combination when liquid freezing between liquid, and thus suppress the formation in any this air exclusion gap or space.

And, heat transfer element 30 can move into depression 20 when expecting cooling or heating the processing biopharmaceutical materials be held in container 10, and can reach preferred temperature (such as thawing or cryogenic temperature) time and removed being held in the processing biopharmaceutical materials in container, as shown in Figure 2.This insertion and remove can by such as the telescopic equipment 120(that raises and reduce this heat transfer element such as, motor hoist or man-operated mechanism, carry out as shown in Figure 5).

Heat transfer element 30 can comprise one or more heat transfer liquids and flow through pipeline wherein, to control keeper 15, container 10 and to be held in the temperature of processing biopharmaceutical materials wherein.Pump 110(Fig. 5) controller 100(Fig. 5 can be bonded to), the temperature of the processing biopharmaceutical materials in the container 10 being held in keeper 15 to make the heat transfer liquids stream scalable flowing through heat transfer element 30.Heat transfer element 30(is such as used for the pipeline allowing heat-transfer fluid flow) supplemental heater on its outer surface can be comprised (such as, one or more resistance coil 210, as shown in Figure 8), to keep path to open in (namely not freezing path) between the pool period of the processing biopharmaceutical materials in container 10, thus allow the motion of liquid in depression 30.More specifically, the expansion of the ice of (that is, heat transfer element and between outer surface 22 and inner surface 125) in annular gap can upwards be led by this heater, and non-permitted its outer surface 22 or cave structure element 25 are out of shape.Such as, supplemental heater can connect an interval does not have ice when refrigeration operation starts to keep fluid passage, thus for otherwise once freezing will catch to provide with the ring-shaped liquid of pressurized leave path.Alternatively, (such as, probe 200, can utilize the heating element heater replaced on the surface of heat transfer element as shown in Figure 8) to comprise the separate probe of heating element heater.This separate probe can be sized to the fluid passage maintained between hollow center and the end face of ice and open.In another unshowned example, this supplemental heater or probe can be used for wherein preserving the container of processing biopharmaceutical materials (such as, container 10) inner, to make for otherwise once processing biopharmaceutical materials is freezing limited and ring-shaped liquid processing biopharmaceutical materials that is pressurized will provide and leave path.Optionally, the independent probe (probe 200 such as shown in Fig. 8) accommodating heating element heater can be used, to replace the heating element heater be positioned on the surface of heat transfer element.The size of this independent probe can be set as that the fluid passage maintained between the center of depression and ice top surface is in open mode.In another unshowned example, this supplemental heater or probe can be used in the inside of the container (i.e. container 10) wherein maintaining processing biopharmaceutical materials, be maintained for ring-shaped liquid processing biopharmaceutical materials to make leaving path, otherwise words once processing biopharmaceutical materials is freezing, this leaves path can blocked and pressurized.

Heat transfer element 30 can have finger, comprises top common segment or track 31 and one or more finger piece 32, and finger piece 32 is to downward-extension and have the shape of the shape that to conform to depression 20 as shown in Figure 3.Finger piece can be tapered towards depression from track, with make insert and remove easier.And heat exchanger can be configured to promote the heat transfer on vessel side of each finger piece and suppress the heat transfer on opposition side, such as, via the insulation on opposition side.

As mentioned above, heat transfer element 30 cools by making heat transfer fluid circulation pass its inner passage and heats.Such as, silicone oil, such as Dow Syltherm HF, can be used as heat-transfer fluid in the temperature range of about-70 DEG C to+40 DEG C.The temperature of heat-transfer fluid and flow velocity can by peripheral equipment controls, such as recycle cooler, such as Sartorius Stedim Biotech CU5000 thermal control units.In the example of shown in Fig. 7, finger piece 32 comprises the coil pipe 33 be received in one or more depression 20 as shown in the cross-sectional view of this accompanying drawing.As mentioned above, track 31 can connect each finger piece extended thus.Finger piece can be formed by such as rustless steel.And this pipeline (such as heat transfer element 30) directly can insert depression 20 and maybe can be encapsulated in protective housing, and housing inserts depression 20.

Alternatively, replace allowing liquid flow through heat transfer element, heat transfer element is undertaken evaporating and flowing cooling by making the cryogen (such as liquid nitrogen, liquid argon or liquid carbon dioxide) flowing through its inner passage.And heat transfer element cools by making the cold-producing medium (such as R-507) flowing through inner passage evaporate and flow.And heat transfer element can by resistive heater heats.

Heat transfer element alternatively can by providing the element of high-termal conductivity to cool between finger piece and active cooling/heating region and heating.The example of high-termal conductivity element comprises heat pipe and anisotropic graphite sheet.

The depression 30 of keeper 15 can be tapered to make heat transfer element 30 be easy to insert and remove from opening.And as mentioned above, keeper 15 can be meshed with base portion 17 or engage or be connected, base portion 17 has multiple depression or groove 117 for receiving the bottom 119 with support holder 15.Base portion 17 can construct (be such as shaped and determine size) is transported by allowing the keeper 15 wherein with container 10 to handle equipment (such as supporting plate jack and fork truck) by conventional supporting plate.

In one example, before processing biopharmaceutical materials in the container 10 be held in keeper 15 is freezing, keeper 15(is its outer surface 22 such as) can be towards its inside (i.e. chamber 50) spill, to make when fluid pressure loads the wall (namely due to freezing effect) of keeper 15, wall outwards bends to form the shape being roughly rectangular prism.The degree of spill can change along with the height of box, to compensate due to this freezing change of error caused.

Keeper 15 can have cover plate 60 to provide the completely closed of container/cartridge assembly.Cover plate can above one or be separated.Keeper 15 and/or the depression 30 being connected to this can have insulating barrier, alternatively on the outer surface to minimize the variations in temperature of In transit.Insulating barrier can be removable or fixing.Insulating barrier can be embedded in double-walled construction alternatively.

Although container 10 can have any useful geometry, in one embodiment, container is the rectangular prism with angle brace structure, such as Sartorius Stedim Biotech Flexel 3D.The width of container on the axis perpendicular to heat transfer element 30 plane is specific, to produce the heating and cooling response of expectation.Such as, the width comparable degree of depth or highly much smaller, with the time needed for the content minimizing freezing or Defrost vessel.But, the degree of depth and highly usual due to store and shipment/manipulation aspect consideration and be limited to the actual maximum of about 1 meter.In one example, container (such as container 10) can be 23.25 inches × 7.87 inches × 42 inches.The volume available and 15% with about 110 liters expand and safety margin by this container.

Container 10 can be formed by the laminated film comprising multilamellar.And the bio-compatibility product contact layer of flexible container 10 inside can be formed by such as low sealed polyethylene, very low sealed polyethylene, ethylene-vinyl acetate copolymer, polyester, polyamide, polrvinyl chloride, polypropylene, polyvinyl fluoride, polyvinylidene fluoride, polyurethane or PEP.Gas and water vapour barrier layer also can be formed by the ethylene/vinyl base alcohol copolymer mixture in polyamide or ethylene-vinyl acetate copolymer.And flexible container 10 can comprise the layer (such as polyamide) with high mechanical properties, and comprise the skin (such as, polyester) thermal weld to insulating effect.These layers can be compatible with hot and cold condition, and can bear ionization and the gamma-ray irradiation of sterilization object.

Container 10 can be suitable for receiving and comprising freezing and/or liquid biopharmaceutical material.In one embodiment, processing biopharmaceutical materials can comprise protein solution, protein formulation, Freamine Ⅲ, amino acid preparation, peptide solution, peptide preparation, DNA solution, DNA preparation, RNA solution, RNA preparation, nucleic acid solution, nucleic acid preparation, antibody and fragment thereof, enzyme and fragment thereof, vaccine, virus and fragment thereof, biological cell suspensions, biological cell fragment suspension (comprises organelle, inclusion body, memebrane protein, and/or film), tissue fragments suspensions, cell aggregation liquid suspension, biological tissue in solution, organ in solution, embryos in solution, cell growth medium, serosity, biological product, blood products, preserve solution, fermented product and there is or do not have the cell culture fluid of cell, the mixture of above material and biocatalyzer and fragment thereof.

As mentioned above, container 10 can construct (be such as shaped and determine size) for will be received in keeper 15, and keeper 15 is used as the protector of supporting flexible container 10, supporting construction or framework, as Figure 1-5.Keeper 15 can be configured between the filling of processing biopharmaceutical materials, transport, storage and/or pool period, protect the container be held in wherein.Such as, keeper 15 can be kept by heat transfer element 30 in processing biopharmaceutical materials and protect container 10 between pool period.

And container 10 and/or keeper 15 can be equipped with one or more temperature sensor (not shown) alternatively to be changed with detected temperatures, thus the freeze/thaw process of processing biopharmaceutical materials in monitoring of containers 10.Sensor can single use, may install, or they can re-use before sterilization.This sensor such as can be positioned chamber wall (that is, inner surface 40) and goes up and can be bonded to controller.And container 10 and/or keeper 15 can be equipped with one or more heat-flow sensor (not shown) alternatively to quantize the speed that heat energy entered or left container.

In another example, one or more temperature sensor can be positioned in one or more depression 20 to measure the temperature of the liquid of pocket interiors.This sensor can be bonded to controller and be used for determining when heat exchanger can remove (such as, via elevator) from depression after freezing.This sensor can be installed on heat exchanger to minimize the instrument on keeper 15.One or more sensors (such as, sensor 116) in addition can be used to determine whether that heat exchanger (such as, heat transfer element 30) is seated in depression completely.This sensor will be installed on heat exchanger ideally to minimize the instrument on keeper 15.

In another example, sensor can determine whether whether the annular space in the depression 20 between heat exchanger and the outer surface 22 of keeper 15 and/or the inner surface 125 of each structural detail 25 is full of completely by (such as, by water or another liquid).This sensor (sensor 117 such as, in Fig. 5) can be installed on heat exchanger (such as one or more heat transfer element 30) to minimize the instrument on keeper 15.If this sensor measures the pressure transducer of fluid level by being associated with fluid pressure, so sensor can be positioned for liquid (such as water) being moved into depression and from the pipeline wherein removing (such as via manifold 31).And keeper 15 can have alternatively for the fixing position of data logger.

And, those skilled in the art will appreciate that various keeper (such as keeper 15) can have the chamber (such as chamber 50) being constructed (be such as shaped and determine size) to receive various sizes container (such as container 10).Although container is described as flexible container here, container can be made up of semi-rigid material such as polyethylene etc.An example of this container can comprise the container being similar to standard plastic milk jug.The container be made up of this similar semi-rigid material can have benefited from such as by additional rigidity that attachment (such as regularly or releasedly) to keeper provides.And, no matter by rigidity, flexible or semi-rigid material is formed, container all comprises can the outer surface of inner surface of contact holder (such as keeper 15), described keeper can be formed by so a kind of material, its be convenient to be held in be bonded to Temperature-controlled appliance (such as heat transfer element 30) this keeper (such as keeper 15) in container (such as container 10) conduct heat.Further, this container can have various shape, comprises conical by its shape (such as, the closing end towards the receiving vessel of keeper), to improve the efficiency of freeze/thaw motion and the top be orientated towards container of being expanded by ice.And this container can be such as the flexible container (two films be namely attached to one another) of two dimension shaping or the container of three-dimensional taper.

In another embodiment shown in Fig. 9-11, keeper 415 can be connected to other keepers 416 one or more, and its possessive construction (be such as shaped and determine size) is receive the flexible container for receiving biological vegetable material, such as above-mentioned flexible container 10.Especially, keeper 415 can receive two depressions (or sleeve) 420 along its relatively longitudinal side in keeper chamber 450, and they can be separated with keeper 415 or connect.Container 10 can be received between the depression 420 in the core 451 in chamber 450.Further, container 10 can be configured as the wall 417 corresponding to keeper 415.

Each depression 420 can construct (be such as shaped and determine size) for receive one or more heat transfer element in its chamber 421, such as above-mentioned heat transfer element 30.As shown in figs. 9-11, chamber 421 can from first end 422 opening of keeper 415 to opposite end 423.In another example, chamber 421 can comprise the part of separation, such as above-mentioned depression 20.One or more heat transfer element can be received in chamber 421.Depression 420 can have the wall 425 more flexible and/or thinner than the wall 417 of keeper 415.And the comparable wall 425 of wall 417 more insulate thus suppresses the heat transfer from keeper 415.Keeper 415 and depression 420 can be formed by such as plastics or rustless steel.Keeper 415 and depression 420 are formed by rotational moulding.

As above relative to described in keeper 15 and depression 20, depression 420 can receive heat transfer element 30 to control the temperature of the container 10 be received in chamber 350.Depression 420 can be configured to keep flowing fluid ratio as water, to keep solid/liquid mixture and/or to keep solid such as ice.Compared with the above-mentioned distributing manifold 31 relative to depression 20, liquid can use dip-tube introduce each depression 420 chamber 421 and from wherein removing.Be received in the chamber 450 of contact depression 420 at container 10 while, the temperature being held in the processing biopharmaceutical materials in container 10 controls, relative to the description of the heat transfer element 30 be received in depression 20 above being similar to by the temperature controlling the heat transfer element 30 be received in depression 420.

As shown in figs. 9-11, keeper 415 does not have cover plate, but each preservation part 416 comprises this cover plate 460.Keeper 415 also can receive this cover plate, and cover plate construction is sealing and protects the container 10 be received in chamber 450, and is configured to allow maintenance wherein to have the transport of the keeper 415 of the container 10 of processing biopharmaceutical materials.

Another example is shown in Figure 12-14, and this is the modification of above-mentioned keeper 415.Especially, keeper 515 can construct (be namely shaped and determine size) is receive flexible container for receiving processing biopharmaceutical materials, than flexible container 510 as shown in fig. 13 that.Container 510 can comprise the filling near the low side 516 being connected to container 510 and drain pipeline 514.

Keeper 515 can receive three depressions (or sleeve) 520 along its relatively longitudinal side in keeper chamber 550, and they can be separated with keeper 515 or connect.More specifically, the first depression 621 can be orientated as contrary with the 3rd depression 623 with the second depression 622.Second depression 622 can be separated by heavy connection of pipe 624 with the 3rd depression 623.When container 510 is received in the core 651 in the chamber 650 of keeper 515, pipeline 514 can be received in heavy connection of pipe 624.Keeper 515 also can comprise door 655, and it allows to lead to the pipeline 514 be held in heavy connection of pipe 624.

In another unshowned example, the keeper being similar to keeper 515 can comprise heavy connection of pipe and not allow the door that leads to outside keeper wherein.Alternatively, the pipeline of this container can insert heavy connection of pipe from the opening its top side.Such as, this heavy connection of pipe can be groove in the sidewall of this keeper or groove.In an example again, the keeper being similar to keeper 515 can comprise and leaves opening to allow pipeline through wherein.This pipeline can be connected to the outside of keeper to suppress the damage to this pipeline via any connected mode.

The typical process of a kind of process and/or preservation processing biopharmaceutical materials is as described below.One or more container (such as container 10) is received in keeper (such as keeper 15, keeper 415, keeper 515), as shown in drawings.Liquid biopharmaceutical material can introduce container 10 through pipeline.Heat exchanger (such as heat transfer element 30) inserts depression (such as depression 20, depression 420, depression 621, depression 622, depression 623), and depression can be full of by water.Heat exchanger is cooled (such as by allowing heat-transfer fluid flow through wherein), until the content of container is frozen or its content is in preferred temperature so that transport and storage.The liquid of the encirclement heat transfer element in depression can be first freezing, and form ice bridge between heat exchanger and depression wall (such as outside 22 and inner side 125).At the end of freezing processing, heat exchanger can heat up momently (such as via heat transfer element 30 or supplemental heater 210) until the ice in annular gap melts.Heat exchanger is removed from depression by elevator or other elevation mechanism.Liquid removes from depression via such as manifold or dip-tube.Then keeper 15 can remove from the pedestal of receiving heat-exchanger.

In one example, the content of mixer 10 can be expected, or between processing biopharmaceutical materials frost free period in container 10 or afterwards.Mixing can increase Thawing Rate and improve homogeneity.This mixing performs by various method.In one example, the container 10 be held in keeper (such as keeper 15, keeper 415, keeper 515) can stir (namely moving), to produce the motion of internal tank.Motion can be random, periodic, etc.The path of this motion can be linear, rail type, etc.In another example, recirculation can be performed.Particularly, liquid can on one point place from container pumping and another point introduce, pass through distributing manifold alternatively.In another example, vibration mixing can be carried out.Especially, the probe being connected to axle is orthogonally driven along the long axis of axle with periodicity linear course, and probe has the plate with one or more angled aperture.Angled aperture in plate defines the one-way flow in liquid.Probe can be freezing in original place, and then heat to form the empty working volume not having ice when thawing and starting.Probe is single use ideally, to avoid the complexity can inserting sterile chamber again with probe.In the end in an example, propeller (or impeller) can be freezing in original place, and heat to form the empty working volume not having ice when thawing and starting.Propeller ideally single use to avoid to insert the complexity of sterile chamber with propeller again.

And the content of keeper (such as keeper 15, keeper 415, keeper 515) and container 10 can be monitored via above-mentioned watch-dog and/or temperature sensor, pH sensor or the sensor for any characteristic monitoring the processing biopharmaceutical materials be held in wherein during whole above-mentioned technique.The data corresponding to monitoring can be stored on the storage medium (such as computer disk, processor, flash memory etc.) of controller or computing unit, and it can be sent to computing unit subsequently in order to analyze.Alternatively, watch-dog can be bonded to computing unit (such as, via computer cables or wirelessly) during processing step.And above-mentioned step of thawing can complete via various mixed mechanism as above.

From the above description, those skilled in the art will appreciate that container described here can be suitable in the keeper of various shape or size.And keeper can be suitable for the container receiving various shape or size.These keepers or supporting construction can be configured to the long-term or short-term storage of container under liquid or freezing state comprising processing biopharmaceutical materials, or can be suitable under liquid or freezing state, transport the flexible container comprising processing biopharmaceutical materials.And these keepers and container can be suitable for using together with the other materials outside processing biopharmaceutical materials.

Although the present invention has here illustrated in detail and has described, but to those skilled in the art obviously, various modification, increase, to substitute etc. and to make under spirit of the present invention and therefore these are all considered as being in the present invention's scope as defined by the appended claims not departing from.

Claims

1. one kind for system (5) that is freezing or processing biopharmaceutical materials of thawing, and described system comprises:

For preserving the case (10) of processing biopharmaceutical materials wherein;

There is the keeper (15 in the keeper chamber (50,450,550) for receiving described container (10), 415,416,515), wherein said keeper (15,415,416,515) multiple depressions (20 that its inner surface (125) defines described keeper chamber (50,450,550) are comprised, 420,621,622,623);

Described multiple depression (20,420,621,622,623) contacts the outer surface of described case (10), and described multiple depression (20,420,621,622,623) comprises pocket cavity (122,421) respectively;

For controlling multiple heat transfer elements (30) of the temperature of the processing biopharmaceutical materials be held in described case (10) on one's own initiative, wherein said multiple heat transfer element (30) is received in pocket cavity (22) respectively.

2. system according to claim 1 (5), also comprises the mechanism (120) that structure inserted relative to described pocket cavity (122) and remove described heat transfer element (30).

3. system according to claim 1 (5), wherein said depression (20,420,621,622,623) is included in the opening (23) for receiving described heat transfer element (30) on its top.

4. system according to claim 1 (5), wherein said depression (20,420,621,622,623) be configured to keep liquid wherein, described liquid promotes at the described heat transfer element (30) be received in described pocket cavity (122,421) and described keeper (15,415,416,515) heat transfer between, to control the temperature of the processing biopharmaceutical materials be held in described container (10).

5. system according to claim 1 (5), wherein said keeper (15,415,416,515) keeper wall (40) is comprised, described keeper wall (40) when processing biopharmaceutical materials is in liquid state towards described keeper chamber (50,450,550) in spill.

6. system according to claim 1 (5), also comprises for determining when described heat transfer element (30) is properly positioned to the alignment sensor (116) in described pocket cavity (122,421).

7. system according to claim 1 (5), also comprises for determining the sensor when described pocket cavity (122,421) is filled fully by liquid.

8. system according to claim 1 (5), also comprise the supplemental heater (210) of separating with described heat transfer element (30), it makes described pocket cavity (122,421) liquid in heats up during refrigeration operation, maintain the passage not having ice, thus formed be used for a part of liquid leave path.

9. one kind for system (5) that is freezing or processing biopharmaceutical materials of thawing, and described system (5) comprising:

For preserving the case (10) of processing biopharmaceutical materials wherein;

There is multiple depression (20,420,621,622,623) keeper (15,415,416,515), described multiple depression (20,420,621,622,623) outer surface of described case (10) is contacted, described multiple depression (20,420,621,622,623) each depression (20,420,621,622,623) pocket cavity (122,421) is comprised;

Described keeper (15,415,416,515) there is the keeper chamber for receiving described case, described multiple depression comprises and defines described keeper chamber (50,450,550) inner surface, described inner surface comprises two contact surfaces of the opposite sides contacting described case;

10. system according to claim 9 (5), wherein said multiple depression (20,420,621,622,623) each depression (20,420,621,622,623) be included in the opening for receiving heat transfer element (30) on its top, described heat transfer element is used for the temperature that control is held in the processing biopharmaceutical materials in described container (10).

11. systems according to claim 10 (5), wherein said multiple depression (20, 420, 621, 622, 623) each depression (20, 420, 621, 622, 623) be configured to keep liquid wherein, liquid is received in described pocket cavity (122 at described heat transfer element (30), 421) promote time be received in described pocket cavity (122, 421) the described heat transfer element (30) in and each depression (20, 420, 621, 622, 623) heat transfer between wall (425), to control the temperature of the processing biopharmaceutical materials be held in described case (10).

12. systems according to claim 9 (5), wherein said keeper (15,415,416,515) keeper wall (417) is comprised, described keeper wall (417) when processing biopharmaceutical materials is in liquid state towards described keeper chamber (50,450,550) in spill.

13. systems according to claim 9 (5), wherein said keeper (15,415,416,515) keeper wall (50,450 is comprised, 550), described keeper wall is spill towards each other when processing biopharmaceutical materials is in liquid state.

14. systems according to claim 9 (5), wherein said multiple depression (20,420,621,622,623) each depression (20,420,621,622,623) tapered from described opening, to be easy to the insertion of described heat transfer element (30) and to remove.

15. for a method that is freezing or processing biopharmaceutical materials of thawing, described method comprises:

The case (10) preserving processing biopharmaceutical materials is received in the keeper chamber (50,450,550) of keeper (15,415,416,515);

Keeper (15,415,416,515) multiple depressions (20,420,621,622,623) outer surface of described case (10) is contacted, wherein said multiple depression (20,420,621,622,623) pocket cavity (122,421) is comprised respectively;

Multiple heat transfer element (30) is received in respectively in pocket cavity (122,421); And

Control the temperature of multiple heat transfer element (30) on one's own initiative, to control the temperature of the processing biopharmaceutical materials be held in case (10).

16. methods according to claim 15, also comprise and insert the liquid into pocket cavity (122,421), and wherein the temperature of Heat Transfer Control element (30) is comprised with frozen biopharmaceutical material to the control of temperature, and the freezing of liquid is caused to the control of temperature thus promotes heat transfer element (30) and depression (20,420,621,622,623) heat transfer between wall.

17. method according to claim 15, also comprise and supplemental heater (210) is introduced depression (20,420,621,622,623), to provide the passage not having ice during the refrigeration operation caused by the temperature by Heat Transfer Control element (30).

18. methods according to claim 15, also comprise and supplemental heater (210) is introduced case (10), to provide the passage not having frozen biopharmaceutical material during the refrigeration operation caused by the temperature by Heat Transfer Control element (30).

19. methods according to claim 15, also comprise and insert the liquid into pocket cavity (122,421), and wherein the temperature of control liquid is comprised to promote heat transfer element (30) and depression (20 to the control of temperature, 420,621,622,623) heat transfer between wall, thus the temperature controlling processing biopharmaceutical materials.

20. systems according to claim 1 (5), also comprise the supplemental heater (210) be received in described case (10), to maintain the passage not having frozen biopharmaceutical material in described case (10).

21. according to the system (5) of claim 1-14, wherein said depression (20,420,621,622,623) tapered from described opening, so that heat transfer element (30) can be received in pocket cavity (122 more easily, 421) remove in and from pocket cavity (122,421).

22. according to the system (5) of claim 1-14, and described container (10) and/or keeper (15) also comprise one or more sensor, thus the freezing or course of defrosting of monitoring processing biopharmaceutical materials, change with detecting temperature.

23. 1 kinds as the method as described in arbitrary in claim 15-19, it is used to mixed biologic biopharmaceutical material, and described method also comprises:

Mobile keeper (15,415,416,515) is to cause the mixing of the processing biopharmaceutical materials in case (10).

24. 1 kinds as the method as described in arbitrary in claim 15-19, it is used to mixed biologic biopharmaceutical material, and described method also comprises:

Remove processing biopharmaceutical materials in the primary importance of case (10) from case and be reintroduced back to processing biopharmaceutical materials in the second position of case (10), to cause the mixing of processing biopharmaceutical materials.

25. 1 kinds as the method as described in arbitrary in claim 15-19, it is used to mixed biologic biopharmaceutical material, and described method also comprises:

Mobile mixed organization in processing biopharmaceutical materials in case (10), thus cause the mixing of processing biopharmaceutical materials.

26. methods according to claim 23, wherein said mobile step comprises and periodically moves keeper (15,415,416,515).

27. methods according to claim 23, wherein said mobile step comprises and moves keeper (15,415,416,515) randomly.

28. methods according to claim 23, also comprise and heat transfer element (30) is received in pocket cavity (122,421) in, and the temperature of Heat Transfer Control element (30) is held in the temperature of the processing biopharmaceutical materials in case (10) with control on one's own initiative.

29. methods according to claim 28, also comprise and insert the liquid into pocket cavity (122,421), and wherein the temperature of Heat Transfer Control element (30) is comprised with frozen biopharmaceutical material to the control of temperature, and the freezing of liquid is caused to the control of temperature thus promotes heat transfer element (30) and depression (20,420,621,622,623) heat transfer between wall.

30. method according to claim 28, also comprise and supplemental heater (210) is introduced depression (20,420,621,, thus the passage not having ice is provided during the refrigeration operation caused by the temperature by Heat Transfer Control element (30) 622,623).

31. methods according to claim 28, also comprise and supplemental heater (210) is introduced case (10), thus the passage not having frozen biopharmaceutical material is provided during the refrigeration operation caused by the temperature by Heat Transfer Control element (30).

32. methods according to claim 28, also comprise and insert the liquid into pocket cavity (122,421), and wherein the temperature of control liquid is comprised to promote heat transfer element (30) and depression (20 to the control of temperature, 420,621,622,623) heat transfer between wall, thus the temperature controlling processing biopharmaceutical materials.

33. methods according to claim 25, wherein move mixed organization and be included in traveling probe in processing biopharmaceutical materials, this probe comprises the plate with one or more angled aperture being connected to axle orthogonally, and drives this axle along the long axis of this axle in the mode of linear course.

34., according to the method for claim 33, also comprise the probe be chilled in processing biopharmaceutical materials, and processing biopharmaceutical materials thaw start time heated probe to form the empty working volume not having ice.

35. methods according to claim 25, the step wherein moving described mixed organization is included in rotatable propeller in processing biopharmaceutical materials.

36., according to the method for claim 35, also comprise and carry out freezing to the propeller in processing biopharmaceutical materials, and processing biopharmaceutical materials thaw start time heating propeller to form the empty working volume not having ice.